Method and apparatus for filling needleless injector capsules

ABSTRACT

A method is provided for filling needleless injector capsules with liquid drug, which eliminates or reduces trapped air bubbles in the drug. A two-stage vacuum method is disclosed which enables the capsule to be evacuated rapidly to very low pressure prior to filling. The method is also suitable for filling other small containers with liquids.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase of published PCT Application No.PCT/GB02/00329 filed Jan. 25, 2002 which claims priority to GreatBritain Application No. 0102386.0 filed Jan. 31, 2001 both of whichapplications are incorporated herein in their entirety and to whichapplications is claimed priority.

BACKGROUND OF THE INVENTION

Needleless injectors are devices for delivery liquid drugs through theepidermis of a patient without using a conventional hypodermic needle.The normal principle of operation is to dispense a fine jet of liquidfrom a drug capsule at sufficiently high pressure and velocity to piercethe skin and deposit within the underlying tissues. The better designsof injectors usually have a two-phase injection pressure profile: thefirst is a very fast rise time from zero to a high pressure—typically inthe region of 300 bars—which is the skin-piercing phase, followed by theremaining injectate at a lower pressure, which is sufficient to keep thehoke in the skin open during the injection. The high pressure is usuallydeveloped by a gas spring or pneumatic ram, or sometimes by pyrotechnicmeans.

Typically, the drug capsule is a cylinder with one end open, and theother having the injection orifice. A piston is located within the bore,and the drug is contained between the orifice and piston, the orificebeing sealed temporarily by a rubber plug, cap or other known means.

Drug capsules are often made from a transparent thermoplastic, but athigh strain rate these materials are brittle, and a problem that canoccur during the high pressure phase is that the drug capsule can burst.It is possible to make the wall of the drug capsule sufficiently thickto withstand the burst pressure, but this may result in an unacceptablylarge device which is more difficult to make, and more expensive. Thisproblem is exacerbated by the presence of bubbles of air trapped withinthe capsule after filling. This is th ought to be because of shock wavesproduced by the rapid collapse and expansion of the bubbles during thetransition from the first and second pressure phases. The size of thebubble has an influence—those below about 2 microlitres volume having aninsignificant effect. Larger bubbles, apart from the aforementionedproblem, also compromise the accuracy of filing, so that an incorrectdose might be delivered. Another problem with some drugs, such asadrenaline, is that they are sensitive to the presence of oxygen, and itis necessary to reduce the volume of trapped air to a minimum.

Increasingly, it is preferred that the capsules are pre-filled by themanufacturers on specialized filling machines: this ensures good qualitycontrol, sterility, and traceability, and it follows from the foregoingthat the volume of air trapped in the injectate should be as small aspossible. Equally, low cost production demands high filling rates,typically less than 1 second for 1 ml fill volume. Current fillingmachines for both syringes and needleless injector capsules employvacuum to reduce the amount of air trapped, but the vacuum systemsoperate at around 15 to 20 mbar or higher, which means that asignificant amount of air remains in the syringe or capsule before theliquid drug in introduced. It is possible to design a vacuum systemwhich can operate at lower pressure, but these require very largereservoirs, and consequently extended pump-down times and long fillingcycles. It would be possible to avoid the use of reservoirs and toconnect the capsule to be evacuated directly to a vacuum pump, but thefinal pressure, pumping times, and overall control, would be highlyunsatisfactory except in the most crude applications.

SUMMARY OF THE INVENTION

The present invention is for a two-stage vacuum system which willrapidly evacuate needleless injector drug capsules, syringes and thelike to low pressure prior to filling, without requiring cumbersome andinconveniently large reservoirs. In an advance over the prior art, thereare provided reservoirs which may be connected sequentially to thecapsule to be filled, so that the pressure within the capsule is loweredby pre-determined steps, in a highly repeatable manner, before filling.

According to the present invention there is provided a method of fillinga needleless injector capsule with a material to be dispensed therefrom,which comprises connecting the capsule successively to at least a firstreservoir at a sub-atmospheric pressure and a second reservoir at asub-atmospheric pressure, and thereafter introducing the said materialinto the capsule.

In a preferred embodiment, there is provided a filling head which sealsagainst the orifice of a drug capsule which has a piston or plungeralready assembled therein, or otherwise has the open end sealed againstthe ingress of atmospheric air. Connected to the filling head is avacuum system which first connects the capsule to a vacuum reservoirevacuated in 1 mbar; this raises the pressure of the capsule andreservoir to 15 mbar. This increased pressure within the combinedreservoir and capsule would be too high to ensure minimal volume oftrapped air within a filled capsule, and a second process stage isolatesthe first reservoir and connects the capsule to a second reservoirevacuated to 0.1 mbar. Since the capsule is already at a reducedpressure of 15 mbar, the resulting pressure in the order of 1 mbar isreached very quickly, and the capsule may be filled. A third processstage is to isolate both vacuum reservoirs and open the filling head toatmosphere to allow the capsule to be removed.

The volume of each reservoir is pre-determined in a fixed ratio to thevolume of the capsule, connection pipes, valves and other ancillaryequipment. One or more additional reservoir may be used and connectedsequentially, and the pressures mentioned above are for illustrationpurposes only and may vary according to the application.

BRIEF DESCRIPTION OF THE DRAWINGS

The presently preferred embodiment will now be described with referenceto the accompanying drawings, in which:

FIGS. 1, 2 and 3 show the evacuation sequence for a ten-head filler,(although the present invention is applicable to filling machines withany number of heads); and

FIGS. 4 a, 4 b and 4 c are centre-line cross sections through a suitabletype of filling head an drug capsule of cylindrical form, to show thesequence of evacuation, sealing and filling.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring to FIG. 1, the inlet of vacuum pump 1 is connected via anisolation valve 13 to reservoir 2, and the inlet of reservoir 2 isconnected to a 2-port valve 3. Similarly, vacuum pump 5 is connected viaisolation valve 14 to reservoir 5, the inlet of which is connected tothe 2-port valve 7. The inlets of valves 3 and 7 are connected to thecommon vacuum bus 12. Connected to the vacuum bus 12 are the fillingheads 4, and an air admittance valve 9. Transmitting gauges 10 areconnected to the pipework to provide indications of the pressures duringthe filling cycle, and to transmit control signals to a sequencecontroller 11.

Referring now to FIG. 4 a, a capsule 40 is located with an interferencefit within a sleeve 41. Sleeve 41 has a tubular extension 42, frangiblyconnected at 43, and the extension 42 has a resilient interface seal 47fixed so that it forms a vacuum and liquid-tight seal on the face 49 ofthe capsule 40 and the inner surface of the extension 42. The seal 47 isperforated by a conduit 48 which is in hydraulic and vacuum connectionwith the injection orifice 44 of capsule 40. Sealingly and slidinglylocated within the bore of capsule 40 is a piston 45; its location issuch that the volume 46 between the orifice and the piston is that whichis required to be filled with liquid drug. A filling head 60 is shownsealingly engaged with the extension 42. The filling head 60 has aresilient seal 61 which makes a vacuum-tight seal between the head 60and the rim 50 of the extension 42. A filling tube 63 is located forlongitudinal sliding movement within a vacuum-right tube seal 64. Thefilling tube 63 is provided with a connection 65 for liquid input, andthe filling head 60 is provided with a connection 62 for vacuum. A tipsealing valve 66 is shown sealing the outlet orifice 67 of the fillingtube 64. FIG. 4 a thus shows the position of the capsule and fling headcomponents in a ready-to-evacuate state.

Referring to FIG. 4 b, this shows the filling tube 63 located sealinglyon the interface seal 47, so that the outlet orifice 67 is in vacuum andliquid-tight connection with the conduit 48. This is the position afterevacuation of the capsule 40, and immediately prior to filling withliquid.

FIG. 4 c is similar to FIG. 4 b, except that the tip sealing valve 66 islifted to open the outlet orifice 67. This permits liquid to flowfrom aliquid supply source (not shown) through connection 65, through the boreof filling tube 63, the outlet orifice 67, the conduit 48 and into thevolume 46.

The filling sequence will now be described, starting by reference toFIG. 3. The approximate pressures achieved are for illustration only,and a calculated example will follow.

Stage 1

FIG. 3 shows diagrammatically ten filling heads and capsules 4 (whichare as shown in FIGS. 4 a, 4 b and 4 c) connected in parallel to thevacuum bus. Valve 9 is open, and thus connects the filling heads 4, viabus 12, to the atmosphere via filter 8. During this stage, valves 3 and7 are closed, and the vacuum reservoirs 2 and 6 are being evacuated bypumps 1 and 5 respectively until the required vacuum is reached, whenthe valves 13 and 14 close to isolate the reservoirs 1 and 5. Reservoir2 is evacuated to a pressure of 1 mbar, and reservoir 6 is evacuated toa pressure of 0.1 mbar by vacuum pump 5. Now, referring to FIG. 1, valve9 is then closed, and valve 3 is opened, thus connecting the fillingheads 4 to the reservoir 2 via bus 12. The filling heads and capsulesare as shown in FIG. 4 a. Note that the tip sealing valve 66 is closedto prevent the vacuum drawing out any liquid during the evacuation stageof the cycle.

Stage 2

Referring to FIG. 1, valves 9, 13, 14 and 7 are closed, and valve 3 isopen, thus connecting the reservoir 2 to the filling heads 4 via bus 12.The atmospheric air which was contained in the bus 12 and filling heads4 is therefore expanded to a lower pressure, dependent upon the ratio ofthe volume of reservoir 2 and the volume of the bus 12, filling heads 4and any ancillary equipment such as the gauges 10, say 15 mbar.

Stage 3

This stage reduces the pressure in the filling heads 4 as follows.Referring to FIG. 2, valve 3 is closed, after which valve 7 is opened,and this connects the filling heads 4 to the vacuum reservoir 6 via bus12. Since the filling heads 4 and bus 12 are already at a reducedpressure of about 15 mbar from stage 2, there is a further reduction inpressure to about 1 mbar as the small amount of air in the systemexpands to fill reservoir 6. This expansion is very rapid—much less thanone second for typical small volume containers. During this stage, thevalve 13 may be open to evacuate the reservoir 2 ready for the nextcycle.

When the pressure in the filling heads 4 is sufficiently low, referringto FIG. 4 b, the capsule volume 46 and extension volume 51 are at apressure of 1 mbar, and the outlet orifice 67 of filling tube 63 is nowbrought into sealing connection with the conduit 48 in the resilientinterface seal 47. Liquid connection 65 is connected to a source of theliquid 52 (not shown) to be transferred to the capsule 40. The liquid 52may be at above atmospheric pressure to overcome the resistance to flowof the filling tube 67 and associated pipework. As shown in FIG. 4 c,the tip sealing valve 66 is now opened, and the liquid 52 thus flowsinto the volume 46. The pressure in the volume 46 was 1 mbar, so itfollows that the maximum volume of air that could be trapped within thevolume 46 is one thousandth of the said volume.

Stage 4

Following stage 3, the valve 7 may be closed to allow the reservoir 6 tobe evacuated to the required level. With both valves 3 and 7 now closed,valve 9 is opened to connect the bus 12 and filling heads 4 toatmosphere—i.e. to release the vacuum. It is preferred in pharmaceuticalfilling operations to prevent airborne bacteria and other contaminantsfrom reaching the various parts of the bus, valves and reservoirs, andthe atmospheric air may be taken in via the filter 8. Referring to FIG.4 a, this is the position of each filling head 60 at the end of theevacuation and filling cycle. The head 60 is then removed from theextension 42 of capsule sleeve 41, and a sealing stopper or similardevice is inserted into the bore of the extension 42 to seal against theingress of dirt and bacteria, and to prevent loss of liquid byevaporation. Alternatively, a sealing pin may be inserted in the conduit48. The filled capsule is removed, and the filling and sealing cycle iscomplete.

Transmitting gauges 10 inform the controller 11 that the correctconditions exist for each part of the sequence to begin. A number ofsafety devices such as pressure switches would be used in practicalinstallations, but have been omitted from the description in theinterests of clarity. Also, in a multiple filling head embodiment, itmay be necessary to incorporate isolation valves to each head to preventa malfunction in a filling head causing a massive air leak.

To avoid bubbles being formed in the liquid after filling according tothe present invention, it may be necessary for the liquid to bede-gassed before filling.

As discussed, one of the objectives of the invention is to achievepredictable and repeatable pressures within the capsule prior tofilling, and it may be seen from the foregoing that by sequentiallyconnecting the capsules to fixed volume reservoirs at known pressures,this objective may be achieved. As an illustration, the following is acalculated example of a typical installation, using the FIGS. 1 to 3 and4 a to 4 c as references.

Pressures throughout are calculated using the ideal gas law equation:PV=m/M R.T=v.R.T  (1)

-   NB v may be replaced by n-   Where P=pressure exerted by gas (N/m²)    -   V=volume of gas (m³)    -   n=number of moles present in volume V

$\begin{matrix}{R = {{gas}\mspace{14mu}{constant}\mspace{14mu}\left( {{kJ}\text{/}{{kmole} \cdot K}} \right)\mspace{14mu}{or}\mspace{14mu}\left( {{kNm}\text{/}{{kmole} \cdot k}} \right)}} \\{= {8.3144\mspace{14mu}{kJ}\text{/}{{kmole} \cdot K}}}\end{matrix}$

-   -   T=temperature of gas K

Calculations involving vacuum usually quote pressures in mbar andvolumes in liters, hence:

R becomes 83.14 mbar 0.1 . mole⁻¹. K⁻¹

Now with reference to FIG. 1,

-   -   Let P₁=pressure in reservoir 2    -   V₁=volume of reservoir 2    -   n₁=number of moles of air in reservoir 2    -   T₁=temperature of reservoir 1    -   P₂=pressure in reservoir 6    -   V₂=volume of reservoir 6    -   n₂=number of moles of air in reservoir 6    -   P₃=pressure in vacuum bus    -   V₃=volume of vacuum bus    -   (note that V₃=volume of pipes, gauges, valves and fittings)        Calculation of Vacuum Bus Volume V₃

Let volume of vacuum line connecting filler head+dead space in fillerhead=2 ml thus for 10 filling heads, volume is 2×10=20 ml=0.02 liters

Let volume 46 of capsule 40 and volume 51 of extension 42=1 ml, thus for10 capsules is 1×10=10 ml=0.01 liters

Let the inside diameter of each filling head connecting tube be 500 mm,and the inside diameter be 3 mm. Thus the volume of 1 line is 3534 mm³and 10 lines is 10×3534=35340 mm³=0.0353 liters

Let the volume of the vacuum bus be 0.0035 liters

Total volume V₃=0.0688 liters

Then for Stage 1:

-   [1] number of moles in reservoir 2, n₁-   Let P₁=1×10⁻¹ mbar V₁=5 liters T₁=293° K-   P₁V₁=n₁RT₁

${\therefore n_{1}} = {\frac{1 \times {10^{- 1} \cdot 5}}{83.14 \times 293} = {2.05 \times 10^{- 5}\mspace{14mu}{moles}\mspace{14mu}{air}}}$

-   [2] number of moles in vacuum system (or bus), V₃-   Let P₃=1000 mbar V₃=0.07 liters

${\therefore n_{3}} = {\frac{1000 \times 0.07}{83.14 \times 293} = {0.00287\mspace{14mu}{moles}\mspace{14mu}{air}}}$

-   [3] On release of valve 3, total volume V₃ of the system is V₁+V₃    and therefore the total number of moles is n₅=n₁=n₃    Thus the system pressure P₅ after 1^(st) stage vacuum is

$\frac{n_{5}{RT}_{5}}{V_{5}} = {\frac{\left( {{2.05 \times 10^{- 5}} + 0.00287} \right) \times 83.14 \times 293}{\left( {5 + 0.07} \right)}\mspace{14mu}{mbar}}$∴ pressure in the system after 1^(st) stage evacuation is 13.9 mbarVacuum Stage 2

-   [4] Number of moles in reservoir 6: as V₁=V₂ and P₁=P₂,    n ₂ =n ₁=2.05×10⁻⁵ moles air-   [5] Number of moles n₃ remaining in vacuum system V₅ after 2^(nd)    stage:-   now the pressure in the line P₃=P₅=13.9 mbar,-   and the volume V₃=0/07 liters

${\therefore n_{3}} = {\frac{P_{3}V_{3}}{{RT}_{3}} = {{\frac{13.9 \times 0.07}{83.14 \times 293}\mspace{14mu}{moles}\mspace{14mu}{air}} = {4 \times 10^{- 5}\mspace{14mu}{moles}\mspace{14mu}{air}}}}$

-   [6] Number of moles in system, n₅:    n ₂ +n ₃=2.05×10⁻⁵×4×10⁻⁵=6.05×10⁻⁵=6.05×10⁻⁵ moles air    Thus the final pressure P_(S2) after the 2^(nd) stage evacuation    (i.e. immediately before filling the capsule with liquid), is

$\frac{n_{5}{RT}_{5}}{V_{S}} = {\frac{6.05 \times 10^{- 5} \times 83.14 \times 293}{5} = {0.29\mspace{14mu}{mbar}}}$

This is sufficiently low pressure to ensure that bubbles of air trappedwithin the liquid are insignificant. Note also that the calculationsassume a perfect system with no leaks and outgassing; in practice verysmall leaks could occur, but the example given would be suitable forfilling a 0.5 ml capsule with a maximum bubble size of about 0.5 μl.

1. A method of filling a needleless injector capsule, comprising thesteps of: connecting a needleless injector capsule to a first reservoirat a first sub-atmospheric pressure and thereby reducing an interiorvolume of the capsule to the first sub-atmospheric pressure; connectingthe capsule to a second reservoir at a second sub-atmospheric pressurewhich is below the first sub-atmospheric pressure and thereby reducingthe interior volume of the capsule to the second sub-atmosphericpressure; and introducing a liquid drug into the capsule.
 2. The methodof claim 1, further comprising: connecting the first reservoir to asource of sub-atmospheric pressure.
 3. The method of claim 1, furthercomprising: connecting the second reservoir to a source ofsub-atmospheric pressure.
 4. The method of claim 1, further comprising:connecting the interior volume of the capsule to surrounding atmosphericpressure before connecting to the first reservoir and after introducingthe liquid drug, wherein the interior volume of the capsule is connectedto the surrounding atmosphere via a filter.
 5. A method ofsimultaneously filling a plurality needleless injector capsules,comprising the steps of: connecting a plurality of needleless injectorcapsules to a first reservoir at a first sub-atmospheric pressure andsimultaneously reducing interior volumes of each of the plurality of thecapsules to the first sub-atmospheric pressure; connecting the pluralityof capsules to a second reservoir at a second sub-atmospheric pressurewhich is below the first sub-atmospheric pressure and simultaneouslyreducing the interior volume of each of the plurality of capsules to thesecond sub-atmospheric pressure; and introducing a liquid drug into eachof the plurality of capsules.
 6. The method of claim 5, furthercomprising: connecting the first reservoir to a source ofsub-atmospheric pressure.
 7. The method of claim 5, further comprising:connecting the second reservoir to a source of sub-atmospheric pressure.8. The method of claim 5, further comprising: connecting the interiorvolume of each of the plurality of capsules to surrounding atmosphericpressure before connecting to the first reservoir and after introducingthe liquid drug, wherein the interior volume of each of the plurality ofcapsules is connected to the surrounding atmosphere via a filter.